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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5650-5655
Copyright © 2003 by The Endocrine Society

Pegvisomant-Induced Serum Insulin-Like Growth Factor-I Normalization in Patients with Acromegaly Returns Elevated Markers of Bone Turnover to Normal

C. Parkinson, M. Kassem, L. Heickendorff, A. Flyvbjerg and P. J. Trainer

Department of Diabetes and Endocrinology (C.P.), The Ipswich Hospital, Ipswich IP4 5PD, United Kingdom; Department of Endocrinology and Metabolism (M.K.), University Hospital of Odense, Odense DK 5000, Denmark; Departments of Clinical Biochemistry (L.H.) and Medical Research Laboratories (A.F.), Aarhus University Hospital, Aarhus DK 8000, Denmark; and Department of Endocrinology (P.J.T.), Christie Hospital, Manchester M20 4BX, United Kingdom

Address all correspondence and requests for reprints to: Dr. Peter J. Trainer, Department of Endocrinology, Christie Hospital, Manchester, M20 4BX, United Kingdom. E-mail: Peter.Trainer{at}man.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28–78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)2 vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 ± 76 to 242 ± 28 µg/liter, P < 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)2 vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P < 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)2 vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GROWTH HORMONE STIMULATES bone turnover (1) directly in a dose-dependent manner (2, 3), indirectly via the action of IGF-I on bone tissue, and by influencing other regulators of bone metabolism such as vitamin D and PTH (4, 5, 6, 7).

Acromegaly produces distinct morphological skeletal changes, soft tissue enlargement, and abnormalities of calcium-phosphate metabolism (8). Mild hypercalcemia and hypercalciuria are observed due to increased intestinal calcium absorption secondary to enhanced renal synthesis of 1,25-dihydroxy vitamin D [1,25-(OH)2 vit D]. Increased renal tubular reabsorption of phosphate and mild hyperphosphatemia have also been described, presumably reflecting altered PTH activity. These abnormalities may be corrected by pituitary surgery (9) and bromocriptine (10). There is also evidence of increased bone turnover in patients with acromegaly, as judged by biochemical markers of bone resorption and formation (8, 11, 12, 13, 14). Many of the biochemical abnormalities of bone resorption and formation observed in patients with acromegaly improve after transsphenoidal pituitary surgery or dopamine agonists or somatostatin (SMS) analog therapy (15, 16, 17).

Pegvisomant is a GH receptor antagonist that, in doses up to 40 mg/d, is capable of normalizing serum IGF-I in 97% of patients with active acromegaly and, thus, represents the most effective medical therapy for this condition to date (18, 19). GH receptor blockade is a novel treatment strategy, and it remains to be established whether normalization of serum IGF-I during pegvisomant therapy is accompanied by normalization of metabolic derangements that characterize acromegaly. Initial data suggest that this may be the case, with the reported changes in serum lipoproteins (20), cortisol (21), and leptin (22) supporting this notion. One previous study has addressed changes in bone turnover in patients with acromegaly receiving pegvisomant (23). However, the present study differs because it is a prospective analysis using markers of bone formation [osteocalcin (OC), serum amino-terminal propeptide of human type I collagen (PINP), and bone-related alkaline phosphatase(BAP)], bone resorption [type I collagen cross-linked urinary N-telopeptide/creatinine (NTx/Cr) ratio and C-terminal cross-linked telopeptide of type I collagen (CTx)], and soft-tissue formation, as well as calcium, PTH, and vitamin D metabolites, in 16 patients with acromegaly, and it compares these markers with age- and sex-matched controls analyzed in the same single-batch analysis. Additionally, the mean duration of therapy for the present study was 7 months (range, 3–11 months) and all patients normalized IGF-I.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Sixteen patients (nine males; median age, 52 yr; range, 28–78 yr) with an established diagnosis of acromegaly were recruited. The study was approved by the local research ethics committee for South Manchester, United Kingdom, and all subjects provided written informed consent. Thirteen of the 16 subjects had previously undergone pituitary surgery, and 12 had received conventional three-field, external-beam radiotherapy. Three subjects had received only medical treatment before recruitment. Fifteen patients had participated in a double-blind study of daily pegvisomant therapy (18) and, along with an additional patient entered on a compassionate basis, rolled over into an open-label extension study (19). After washout from prior medical therapy (5 wk for dopamine agonist, 2 wk for sc octreotide), all patients had a serum IGF-I value at least 30% above the age-related upper limit of normal. Pegvisomant was commenced at 10 mg/d, with dose increments of 5 mg/d made every 8 wk until serum IGF-I was in the age-related reference range. All patients achieved normalized serum IGF-I on pegvisomant (mean duration of therapy, 7 months; range, 3–11 months; median dose, 20 mg/d; range, 10–40 mg/d). Patients received fixed doses of hormone replacement therapy with glucocorticoids (n = 10), T4 (n = 2), estrogen (n = 2), and testosterone (n = 6) when appropriate.

Control sera were drawn from 32 age- and sex-matched ambulatory individuals. There was no documented evidence of hypogonadism in any of the 20 male controls. Seven of 12 age-matched female controls were postmenopausal. No estrogen therapy was used by control females.

Sera were collected after an overnight fast, at baseline, and again once serum IGF-I was normal, frozen within 2 h of venepuncture, and stored at -80 C. Single-batch measurements of serum amino-terminal propeptides of human type III (PIIINP) and type I (PINP) pro-collagen, OC, BAP, and CTx were undertaken on samples obtained at baseline and the first occasion of serum IGF-I normalization, along with sera from the 32 age- and sex-matched controls. Serum calcium, intact PTH (iPTH), 25-hydroxy vitamin D [25-(OH) vit D], 1,25-(OH)2 vit D, NTx/Cr (24 h collection), and calcium were also measured at these time points (single-batch analysis). Before analysis, samples were thawed, for the first time, at 37 C over 20 min.

Assays

Serum IGF-I was assayed after each visit by a competitive binding RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). The intraassay coefficient of variation (CV) was less than 3%, and the interassay CV was less than 8.4%.

Serum PIIINP was analyzed by a RIA (Orion Diagnostica, Oulunsalo, Finland). The intraassay CV was less than 5%, and the interassay CV was less than 7% (24).

Serum PINP was analyzed by a RIA (Orion Diagnostica). The intraassay CV was less than 8%, and the interassay was less than 8.2% (25).

Serum OC (N-terminal midfragment OC) detects intact OC as well as the large N-terminal midfragment. Analysis was performed by an electrochemiluminescence immunoassay using an automated instrument (Elecsys 2010 immunoassay analyzer; Roche Diagnostics, Mannheim, Germany). The interassay CV was less than 4.5% (26).

Serum ß-crosslaps (CTx) were measured by an electrochemiluminescence immunoassay using an automated instrument (Elecsys 2010 immunoassay analyzer, Roche Diagnostics). The interassay CV was less than 5.8% (27).

The NTx/Cr ratio was measured by a chemiluminescence immunoassay using an automated instrument (Vitros ECI; Ortho-Clinical Diagnostics, Amersham, UK). The interassay CV was less than 8.5%. Creatinine was measured by a colorimetric method using an automated instrument (Hitachi 917, Roche Diagnostics) (28).

Serum iPTH was measured by a solid-phase, two-site, chemiluminescent immunometric assay using an automated instrument (Immulite, DPC, Los Angeles, CA) (29).

25-(OH) vit D was measured by a RIA (Diasorin, Stillwater, MN). The intraassay CV was less than 10%, and the interassay CV was less than 12% (30).

1,25-(OH)2 vit D was analyzed by a radioreceptor assay after extraction and chromatographic purification (Nichols Institute Diagnostics). The intraassay CV was less than 10%, and the interassay CV was less than 14% (31).

BAP was precipitated using a lectin from wheat germ, and the remaining activity in the supernatant was determined by a standard enzymatic method using an automated instrument (Bone-ALP, Hitachi 917; Roche Diagnostics). The interassay CV was less than 7.5% (32).

Statistical analysis

For comparison between controls and patients, the Student’s t test was used, and for non-Gaussian data, the Mann-Whitney rank sum test was used. Changes during pegvisomant were analyzed using the Student’s paired t test or the Wilcoxon signed rank test where appropriate. Calcium clearance was calculated using the following formula: [urine calcium (mmol/liter) x serum creatinine (mmol/liter)]/[urine creatinine (mmol/liter) x serum calcium (mmol/liter)]. Forward stepwise multiple regression was used to analyze the relationships between the measured variables. Statistical significance was assumed for P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figures 1Go and 2Go show baseline levels and levels observed after pegvisomant-induced serum IGF-I for all parameters measured, along with control data where available.



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  		FIG. 1. Levels of markers of bone formation (PINP, OC, and BAP), bone resorption (NTx/Cr and CTx), and soft tissue collagen formation (PIIINP) in 16 patients with active acromegaly compared with 32 age- and sex-matched controls and the effect of pegvisomant (PEG)-induced serum IGF-I normalization. {square}, Baseline; , on pegvisomant; , control. *, P < 0.05; and #, P < 0.001, compared with control. {ddagger}, P < 0.05; **, P < 0.01; {dagger}, P < 0.001; and {dagger}{dagger}, P < 0.0001, compared with baseline. For PINP, BAP, NTx/Cr, and PIIINP, values represent mean, with error bars indicating SEM. For OC and CTX, values represent median, with error bars indicating range.

 


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  		FIG. 2. The effect of pegvisomant-induced serum IGF-I normalization in acromegaly on iPTH, 25-(OH) vit D, and 1,25-(OH)2 vit D. {square}, Baseline; , on pegvisomant. {ddagger}, P < 0.05; and {dagger}, P < 0.001, compared with baseline. For 25-(OH) vit D and 1,25-(OH)2 vit D, values represent mean, with error bars indicating SEM. For iPTH, values represent median, with error bars indicating range.

 
Compared with age- and sex-matched controls, serum PIIINP (mean ± SEM, 3.5 ± 0.2 vs. 4.3 ± 0.3 µg/liter; P < 0.05) was significantly elevated in patients at baseline (Table 1Go ). Pegvisomant-induced serum IGF-I normalization (mean ± SEM, 699 ± 76 to 242 ± 28 µg/liter; P < 0.001) was associated with a significant decrease in this marker of soft tissue formation (PIIINP, 4.3 ± 0.3 to 3.1 ± 0.3 µg/liter; P < 0.01). Using forward stepwise regression, there was a significant correlation between the absolute change in IGF-I and PIIINP (r = 0.7, P < 0.01) (Fig. 3Go).


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  		TABLE 1. Changes in markers of bone turnover and soft tissue formation after pegvisomant-induced serum IGF-I normalization in 16 patients with acromegaly

 


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  		FIG. 3. The relationship between the change in serum IGF-I and the change in PIIINP levels in patients with active acromegaly (r = 0.7, P < 0.01).

 
Compared with age- and sex-matched controls, OC [median (range), 21.6 (14–58) µm/Liter vs. 47 (14–109) µg/liter; P < 0.001] and CTx [median (range), 0.2 (0.04–0.9) pmol/liter vs. 0.8 (0.2–2.4) pmol/liter; P < 0.001] were also significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization was associated with a significant decrease in the markers of bone formation [PINP, 70 ± 12 to 38 ± 8 µg/liter, P < 0.01; OC, 47 (14–109) to 21 (10–73) µg/liter; BAP, 147 ± 29 to 120 ± 23 µ/liter, respectively, all P < 0.05] and markers of bone resorption [CTx, 0.8 (0.2–2.4) to 0.4 (0.03–1.3) pmol/liter, P < 0.0001; NTx/Cr ratio, 92 ± 27 to 56 ± 14, P < 0.01]. Serum IGF-I normalization was associated with a significant decrease in 1,25-(OH)2 vit D (96.4 ± 9.8 to 71.5 ± 5.4 pmol/liter, P < 0.01) and an increase in iPTH [4.45 (1.9–40.2) to 6.0 (2.8–46.7) pmol/liter, P < 0.05], but 25-(OH) vit D levels remained unchanged (30.3 ± 3.5 to 33.8 ± 4.0 nmol/liter). Calcium clearance decreased significantly from 17.32 ± 2.08 to 12.06 ± 1.9 (P = 0.03). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any of the parameters measured for which control data were available.

Univariate analysis at baseline and after the normalization of serum IGF-I revealed no linear correlations between IGF-I, iPTH, or 1,25-(OH)2 vit D and all of the parameters measured. Further investigation of the determinants of individual markers of soft tissue and bone turnover was undertaken using forward stepwise regression, with age, sex, IGF-I, iPTH, and 1,25-(OH)2 vit D entered as independent variables (Tables 2Go and 3Go). At baseline, a significant correlation was observed between iPTH and PINP (r = 0.6, P = 0.02), BAP (r = 0.9, P < 0.0001), and NTx/Cr (r = 0.9, P < 0.0001) and between age and both PINP and OC (r = -0.9, P < 0.05 and r = -0.8, P < 0.05, respectively). After the normalization of serum IGF-I, significant correlations were observed between iPTH and PINP (r = 0.5, P < 0.01), OC (r = 0.6, P = 0.02), BAP (r = 0.7, P < 0.01), and NTx/Cr (r = 0.8, P < 0.0001). After serum IGF-I normalization, gender was also observed to influence PINP levels, with a combination of iPTH and age accounting for 71% of the variance in PINP.


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  		TABLE 2. Forward stepwise regression analysis

 

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  		TABLE 3. Forward stepwise regression analysis

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
One previous study has reported a reduction of bone markers in patients with acromegaly receiving pegvisomant (23). The present study differs from that earlier report in several ways. First, we compared markers of bone metabolism with those of an age- and sex-matched control group in a single-batch analysis. Second, we used several bone formation and bone resorption markers as well as markers of calcium homeostasis (iPTH and vitamin D) and soft-tissue formation (PIIINP). Third, the previous study used samples obtained during a 3-month, double-blind, placebo-controlled study of pegvisomant therapy using 10, 15, or 20 mg/d of pegvisomant, during which not all patients had normalized serum IGF-I (18); whereas in the present study, the normalization of serum IGF-I was a requirement, and the mean duration of treatment was 7 months. In keeping with the report of Fairfield et al. (23), we have observed a significant decline in markers of bone resorption and formation during pegvisomant therapy that persists after a mean of 7 months of treatment. Additionally, the present data highlight the fact that pegvisomant-induced serum IGF-I normalization in acromegaly is associated with the normalization of elevated markers of bone turnover such as OC and CTx. For the first time, we have demonstrated that elevated levels of PIIINP are also returned to normal by pegvisomant-induced serum IGF-I normalization in acromegaly and have highlighted the effect of pegvisomant on iPTH and vitamin D metabolites.

Produced by osteoblasts, OC is the major noncollagenous protein in bone that participates in bone mineralization and the control of osteoblast functions. The present study confirms the observation of others that, compared with age- and sex-matched controls, OC levels are elevated in patients with active acromegaly (8, 14, 16, 33, 34, 35). In contrast to some reports, we did not observe a significant correlation between OC and GH or OC and IGF-I (36). In keeping with a significant decline after transsphenoidal surgery (33, 36) and during both octreotide and pegvisomant therapy (16, 23), a significant decline in OC during pegvisomant therapy was observed. Moreover, normalization of serum IGF-I in this group was associated with the normalization of OC (17, 33, 37).

Alternative markers of bone formation include the amino (PINP) and carboxyterminal (PICP) propeptides of type I collagen. These are liberated in equimolar quantities during type I collagen formation (38, 39). Serum levels of PICP are elevated in some reported series of patients with acromegaly compared with age- and sex-matched controls and decrease during octreotide therapy (17, 33). As previously described by Fairfield et al. (23), who measured PICP, we observed a significant decline in serum levels of PINP after serum IGF-I normalization. Similarly, a decline in OC and BAP accompanied the normalization of serum IGF-I in the present study, and similar findings have been reported in some (17) but not all (40) therapeutic studies in acromegaly.

Traditionally urinary hydroxyproline (OHP) has also been used to assess bone resorption in patients with acromegaly. However, this marker is of low sensitivity and specificity. In acromegaly, urinary excretion of OHP is elevated and may be 3-fold higher than matched controls (8, 14, 34, 35, 36). Urinary OHP levels are normalized by successful treatment (36), although octreotide in some studies failed to produce any significant change (17). Recently, more specific bone resorption markers, such as urinary NTx have been used. Urinary NTx is elevated and, along with OHP, correlates with IGF-I (8). We observed a significant decrease in urinary NTx/Cr ratio after serum IGF-I normalization. We also studied the serum bone resorption marker CTx and found a similar pattern of change to that of NTx/Cr, with high pretreatment levels and normalization during treatment with pegvisomant.

During short and long-term SMS analog therapy in patients with acromegaly, serum iPTH levels have been observed to increase (17). Intestinal malabsorption of calcium has been suggested as a possible mechanism (17, 40). However, administration of GH to normal volunteers is associated with a decline in PTH and an increase in serum calcium along with some decrease in total and free 1,25-(OH)2 vit D (4). Pegvisomant-induced serum IGF-I normalization was associated with a compatible increase in iPTH and decrease in 1,25-(OH)2 vit D and a significant decline in calcium clearance. Compared with normal controls, serum 1,25-(OH)2 vit D levels are elevated in acromegaly and decline after transsphenoidal surgery (9, 15, 41) and during both bromocriptine and SMS analog therapy (15, 40, 41). These changes may reflect a direct action of GH on renal 1{alpha} hydroxylase activity, and the significant decrease in 1,25-(OH)2 vit D levels and increase in PTH observed in the present study may be secondary to the decrease in renal production of 1,25-(OH)2 vit D.

Bone matrix is composed mainly of type I collagen, and it contains minute quantities of type III collagen (38). Thus, the amino (PIIINP)-terminal propetides of type III collagen formation reflect mainly soft tissue turnover apart from bone. PIIINP levels are elevated and correlate with log-transformed serum GH and IGF-I levels in patients with active acromegaly (33), but so far, changes after treatment have not been documented. Our data confirm the presence of elevated PIIINP in patients with active acromegaly, compared with age- and sex-matched controls, which correlates positively with serum IGF-I and, for the first time, document normalization of PIIINP after pegvisomant-induced serum IGF-I normalization. Significant reductions in objective (ring size) measures of soft tissue swelling are reported during pegvisomant therapy (18), but no correlation was observed between changes in ring size and the decrease in PIIINP in the present study (data not shown).

As stated, GH exerts both direct and indirect effects on osteoblasts and osteoclasts (42, 43). Thus, both markers of bone formation and resorption are affected in acromegaly, and treatment with pegvisomant is associated with normalization of both osteoclast and osteoblast activities. We used serum IGF-I as a biological indicator of the normalization of disease, but changes in serum levels of IGF-I were not correlated to changes in biochemical markers of bone formation or bone resorption. This may suggest that local tissue levels of IGF-I are the main determinant of bone turnover. Alternatively, a direct action of GH on bone, independent of IGF-I levels, may account for the changes in bone markers observed. Unfortunately, the design of the current study does not allow the dissection of the relative contributions of GH and IGF-I on bone metabolism in acromegaly. However, forward stepwise regression analysis suggested a significant correlation between iPTH and numerous markers of bone turnover (PINP, BAP, and NTx/Cr) at baseline. After the normalization of serum IGF-I, a significant correlation between iPTH and these same markers, as well as OC, was observed. Although speculative, these data may imply a significant indirect effect of GH on bone markers by modulating PTH.

An alternative mechanism by which pegvisomant may influence bone turnover is through the modulation of 11ß hydroxysteroid dehydrogenase (11ßHSD1) activity, which is partly inhibited by GH. Blockade of GH action in patients with acromegaly is associated with increased cortisone to cortisol conversion (21). Administration of carbenoxolone, a known inhibitor of 11ßHSD, to normal volunteers produces a decrease in bone resorption markers but not bone formation markers (44). Induction of 11ßHSD1, it is postulated, would therefore lead to an increase in bone resorption but not formation markers. Because a significant decline in both formation and resorption markers was observed during pegvisomant therapy, we do not believe that modulation of 11ßHSD1 activity is a major determinant of bone turnover in patients with active acromegaly who receive pegvisomant.

In conclusion, the data presented here indicate the following: 1) patients with active acromegaly have increased bone turnover and soft tissue formation as revealed by significantly elevated PIIINP, OC, and CTx levels compared with age- and sex-matched controls; 2) pegvisomant-induced serum IGF-I normalization in patients with acromegaly produces changes in serum and urinary bone markers, as well as iPTH and vitamin D metabolism, in keeping with and entirely compatible with those observed after conventional therapies; 3) normalization of serum IGF-I by pegvisomant is not only associated with a reduction in markers of bone turnover but also returns many of these markers (PIIINP, OC, and CTx) to normal and is associated with the normalization of serum markers of soft tissue formation; and 4) these changes are maintained in patients receiving pegvisomant for over 6 months.


   Acknowledgments
 
We thank Christine Smith and Margaret E. Roberts for conducting patient visits and collecting serum samples. We also thank Mrs. Karen Mathiassen and Kirsten Nyborg for excellent technical assistance.


   Footnotes
 
A.F. is supported by grants from the Danish Medical Research Council (Grant 9700592), the Novo Foundation, the Aage Louis-Hansen Memorial Foundation, the Nordic Insulin Foundation, the Eva and Henry Frænkels Memorial Foundation, and the Aarhus University-Novo Nordisk Center for Research in Growth and Regeneration (Grant 9600822). P.J.T. and C.P. have received research funds from Sensus Drug Development Corporation and Pharmacia UK.

Abbreviations: 1,25-(OH)2 vit D, 1,25-Dihydroxy vitamin D; 25-(OH) vit D, 25-hydroxy vitamin D; 11ßHSD1, 11ß hydroxysteroid dehydrogenase; BAP, bone-related alkaline phosphatase; CTx, C-terminal cross-linked telopeptide of type I collagen; CV, coefficient of variation; iPTH, intact PTH; NTx/Cr ratio, urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio; OC, osteocalcin; OHP, hydroxyproline; PICP, carboxyterminal propeptide of type I collagen; PIIINP, procollagen III amino-terminal propeptide; PINP, type I procollagen amino-terminal propeptide; SMS, somatostatin.

Received May 7, 2003.

Accepted September 5, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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